Complex oligosaccharides are widely recognized to play a critical role in a host of important biological interactions including protein folding, the immune response, cellular recognition, and host-pathogen interactions. Despite their importance, our understanding of the molecular basis of carbohydrate function lags far behind our knowledge of proteomics and genomics. This is predominantly due to a scarcity of homogeneous, well-defined carbohydrates to serve as standards for glycomics analysis. Biological systems produce oligosaccharides as complex and often intractable mixtures, leaving chemical synthesis as the only avenue for the production of homogenous material for study. For a number of reasons, carbohydrate synthesis remains a formidable challenge, despite numerous advances in recent years. Among the issues which plague carbohydrate synthesis, controlling selectivity of glycosylation reactions is one of the most difficult, largely because most methods for chemical glycosylation reactions rely heavily on the substrates to control the diastereoselectivity. In many cases it is difficult to obtain the desired linkages with good selectivity without extensive modifications to both coupling partners, to obtain a “matched” pair. In the absence of native functionality that permits the introduction of directing groups, the problem is greatly magnified. Stereoelectronic effects can be used to facilitate formation of certain linkages, but to date few robust methods to synthesize difficult linkages without recourse to chiral auxiliaries, temporary prosthetic groups, or de novo synthesis exist. These latter approaches necessarily introduce additional steps into carbohydrate synthesis, and they often do not guarantee selectivity with a broad range of substrates.
Compounds comprising so-called “difficult linkages” such as β-linked 2-deoxy-sugars are often essential for the bioactivity of many natural products, including, for example, digitoxin, mithramycin, and landomycin A. Furthermore, oligosaccharides composed of deoxy-sugars have been shown to possess potent biological activity. Altering the composition of these sugars can modulate a natural product's bioactivity, potentially reducing undesirable side effects. This approach has yet to be broadly adapted to drug discovery, however, as these linkages are considered to be among the most challenging to synthesize directly.
Methods for the direct construction of β-linked phenolic glycosides and thioglycosides of 2-deoxy-sugars have been described, but reports of the direct stereoselective synthesis of β-linked 2-deoxy-sugar disaccharides and oligosaccharides are exceedingly rare. Moreover, the mechanistic basis of selectivity in these latter reactions has yet to be elucidated, and selectivity does not always translate well between systems.
Consequently, there is a pressing need for robust and selective glycosylation reactions that work with a range of carbohydrates.